Theiler~s murine encephalomyelitis virus (TMEV)-inducted demyelinting disease is one of the most relevant of the few available experimental animal modesl of virus-induced demyelination. TMEV are natural mouse pathogens. Intracerebral inoculation of susceptible mouse strains with the BeAn strain of TMEV results in a chronic, progressive, CNS inflammatory demyelinating disorder which is related to life-long persistent CNS virus infection and characterized by spasti hind limb paralysis. Our previous studies have characterized the effector nature, phenotype, repertoire, and specificity of the T cells involved in initiating CNS demyelination and regulating the disease process using antigen-specific tolerance. These studies clearly demonstrate that the demyelination is initiated by virus-specific Th1 cells targeting viral epitopes persistently presented in the CNS. TMEV-induced demyelination is considered a highly relevant animal model for multiple sclerosis (MS) since both diseases are characterized by progressive demyelinating lesions with accompanying mononuclear cell infiltrates in which CD4 plus T cells and activated macrophages predominate. MS is generally considered to involve an autoimmune pathology, but epidemiological evidence strongly suggests a viral trigger. Our preliminary evidence shows that responses to the immunodominant, encephalitogenic CD4 plus T cell epitope on myelin proteolipid protein (PLP139-151) arise in mice 2- 4 weeks after the onset of TMEV-induced demyelination. This proposal will test the hypothesis that the chronic stages of TMEV-induced demyelinationare mediated by CD4 plus T cell responses to both TMEV and to PLP139-151 and perhaps other self myelin epitopes activated secondary to initial myelin damage. The specificity, receptor repertoire, and relative contributions of virus- and myelin-specific T cell and antibody responses to the immunopathologic process at varying stagesof the disease process will be assessed by analyzing both peripheral and CNS- infiltrating T cells. The mechanisms (molecular mimicry vs. Epitope spreading) by which anti-myelin epitope responses arise in these mice will be tested. In addition, we will continue or studies of the efficacy, specificity, and molecular mechanisms by which peripheral tolerance and antagonists of B7/Cd28-mediated costimulation inhibit clinical and histologic disease progression. These studies should define the mechanism(s) by which anti-self responses arise during persistent CNS virus infection and determine their functional contribution to chronic disease pathology. In addition, our studies on specific immunoregulation of TMEV-induced demyelinating disease may be applicable to the understanding the etiology of MS and other chronic (auto) immune diseases and for design of specific treatment strategies.